OBJECTIVES: The major objectives of this research project involve determining the role of epoxide metabolites in the production of cellular and tissue injury, and the elucidation of enzymatic mechanisms of epoxide metabolism. Our more immediate goals have centered on 1) the hepatotoxicity of bromobenzene and substituted bromobenzenes as a model system presumed to involve a chemically-reactive epoxide metabolite, and 2) characterization of the enzymes of the epoxide-diol pathway. Specifically, we were interested in developing, if possible, a firmer basis for an initial rough correlation between the hepatotoxicity of ortho-substituted bromobenzenes (estimated histologically) and the inductive effects of the substituent groups. Since the introduction of substituents onto the bromobenzene could affect one or more of the several enzymatic steps in its metabolism, as well as the intrinsic reactivity of an epoxide metabolite, we also wanted to explore some "substituent effects" on the epoxide-diol pathway as a first step towards the elucidation of enzyme mechanisms. BIOLOGICAL STUDIES: We have refined the histological estimates of the toxicity of ortho substituted bromobenzenes referred to in the proposal, and the results, entirely consistent with our earlier estimates, are presented in Table 2. In addition we have determined changes in SGPT levels caused by administration of our compounds as another independent assessment of their hepatotoxicity. BIBLIOGRAPHIC REFERENCES: In Press: Robert P. Hanzlik, Marsall Edelman, William J. Michaely and Georganna Scott, "Enzymatic Hydration of (O18)-Epoxides. The Role of Nucleophilic Mechanisms." J. Amer. Chem. Soc., 98, 0000 (1976). In Print: Robert P. Hanzlik and Greg O. Shearer, "Transition State Structure for Peracid Epoxidation. Secondary Deuterium Isotope Effects." J. Amer. Chem. Soc., 97, 5231 (1975).